Synthesis of novel guanidino fatty acid esters

ABSTRACT

A METHOD FOR PRODUCING A GUANIDINO FATTY ACID ESTER OF THE FORMULA   H2N-C(=NH)-NH-(CH2)N-COO-R   WHEREIN N IS AN INTEGER OF FROM 3 TO 5 INCLUSIVE AND R IS AN ALKYL GROUP OF 1-7 CARBON ATOMS, ARYL OR ARYLALKYL GROUP, IN WHICH THE AROMATIC RING MAY BE OR MAY NOT BE SUBSTITUTED, WHICH COMPRISES REACTING AN AMINO FATTY ACID ESTER OF THE FORMULA:   H2N(CH2)NCOOR   WHEREIN N AND R ARE AS DEFINED ABOVE, WITH S-METHYL THIOUREA OR CYANAMIDE.

United States Patent 3,652,651 SYNTHESIS OF NOVEL GUANIDINO FATTY ACID ESTERS Setsuro Fujii, 78, l-chome, Kuramoto Shomachi, Tokushima, Japan No Drawing. Filed Oct. 23, 1968, Ser. No. 770,072 Claims priority, application Japan, Oct. 24, 1967, 42/ 68,693 Int. Cl. C07c 101/24 US. Cl. 260-482 R 2 Claims ABSTRACT OF THE DISCLOSURE A method for producing a guanidino fatty acid ester of the formula wherein n is an integer of from 3.to 5 inclusive and R is an alkyl group of 157 carbon atoms, aryl or arylalkyl group in which the aromatic'ring may be or may not be substituted, which comprises reacting an amino fatty acid ester of the formula:

wherein n and R are as defined above, with S-methyl thiourea or cyanamide. 1

This invention relates to the production of w-guanidino fatty acid esters.

The fatty acids as used in the present invention are those fatty acid having 4 to 6 carbon atoms. The ester of such fatty acid is an alkyl (1-7 carbon atoms), arylalkyl or aryl ester wherein the arylalkyl is a benzyl group and the aryl is a phenyl group either of which may have or may not have in the aromatic ring such substituent as, for example, a methylol, methoxy, halogen, carboxyl or nitro group.

In order to obtain the guanidino fatty acid esters of the present invention, a corresponding amino fatty acid ester is reacted with S-methyl thiourea or cyanamide as shown by the following formula:

N32 CNNH r (IS-CH NH; H2N(CH2)nCOOR H NFNHUJHQDCOOR wherein nis 3 to and R is an alkyl, arylalkyl, arylalkyl or aryl group having 1 to 7 carbon atoms and which may be substituted as mentioned before.

Patented Mar. 28, 1972 Ice The guanidino fatty acid esters of the present invention are basic and therefore are preferable to be separated after converting the same into a salt with an acid which can form a salt with a guanidino base. Examples of such acids are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid or carbonic acid, and organic acids such as oxalic acid, tartaric acid or p-toluene sulfonic acid.

The w-guanidino fatty acid esters obtained by the present invention are novel compounds and have action to strongly inhibit the hydrolysis of alginine ester by kallikrein as shown in my concurrently filed patent application Ser. No. 769,815 and therefore are useful for a medicine as an antikallikrein agent.

The present invention will be further explained by referring to the accompanying examples.

GENERAL PROCEDURE An amino fatty acid ester which is the starting material in the process of the present invention may be prepared as follows. Thus, 0.2 mol of w-amino acid, ml. of a corresponding aliphatic alcohol or aromatic alcohol and 150 ml. of benzene are mixed together. The mixture is heated and refluxed while introducing a dry hydrochloric acid gas. The esterification reaction is conducted for 4 to 5 hours. Then the reaction product is concentrated under a reduced pressure and the residue is recrystallized from water, alcohol or acetone to obtain an w-amino fatty acid ester hydrochloride, the ester being an alkyl or arylalkyl ester.

Alternatively, 0.2 mol of an w-amino acid having had the amino group carbobenzyloxylated to be protected -by a known conventional process, 0.2 mol of oor p-substituted phenol, 1 liter of tetrahydrofuran and 0.2 mol of phosphorus oxychloride are mixed together under cooling at l5 C. Then 32 ml. of pyridine are dropwise added thereto under this condition. The mixture is returned to the normal or room temperature after 30 minutes and is left to stand for 1 hour. Then the solution is separated under cooling, and the upper layer is concentrated under a reduced pressure. Then the protected group is removed by the treatment with glacial acetic acid and hydrobromic acid or by palladium reduction to obtain an w-amino fatty acid ester or its hydrobromate.

The w-amino fatty acid ester thus prepared is then dissolved in 200 to 300 ml. of water. To this solution is added 0.1 mol of S-methyl thiourea, and the mixture is allowed to react at 20 to 30 C. for 5 hours. Then the mixture is left to stand at the normal temperature and is ice-cooled after about 20 hours. The precipitated crystals are recovered by filtration and recrystallized from water.

Alternatively the w-amino fatty acid ester is mixed into an aqueous solution of 1 to 10% ammonia in the presence of 10 to 20% cyanamide. The mixture is allowed to react until the final amino ester concentration becomes 30 to 40%. The solution is left to stand at the normal or room temperature or concentrated under a reduced pressure. The crystals formed are recovered and recrystallized from water.

The following compounds were produced in accordance with the above explained General Procedure. In each case the elementary analysis well accorded with the theoretical values.

HzN\ Physical Properties of C-NH-(CHz) JG OR-X M 1 R X Formula HC4H9 H01 72-73 CnHzoNgOgCl H-CgHn HG] 8&86 CmHnzNgOzOl ll-CQHB H01 84-85 C11HQ4N303C1 4 3 n-CH 116-118 C H N O S o 1: 3 s 3 is 31 a a 4 n-C4Hv H2003 95100 C 1H2 Na05 6 4 11-0511 HzCOa 100-107 cnHzsNgos 7 "411-011 94-96CHNOS a la 3 S 3 in as a a A 8 5 n-OiHi 71-72 comNos.

9 5 n-C H H2603 116-113 Clank-[N305 10 4 HlCOa -105 CmHnNgOg 11 5 H100; 101-103 oisHnN o 7 12 a -123 C H N 0 S -OH2 COOH CH3 S0 H What I claim is: 2. The method as claimed in claim 1 wherein the guani- 1. A method for producing a quanidino fatty acid ester of the formula dino fatty acid ester is recovered in the form of a salt with an acid which is capable of forming a salt with the guanidino base.

wherein n and R are as defined above, with S-methyl 45 thiourea or cyanamide.

LORRAINE A. WEINBERGER, Primary Ez zaminer P. J. KILLOS,- Assistant Examiner References Cited f I 0 FOREIGN PATENTS V I 1963 Japan 26 us. c1. X.R. 

